Is SEMA4A p.Asp399Ala (c.1196A>C) pathogenic?

SEMA4A p.Asp399Ala (c.1196A>C) is classified Uncertain significance in SEMA4A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-09). AlphaMissense: ambiguous (0.4004); Very rare (popmax 0.00483%, nfe).

How common is SEMA4A p.Asp399Ala (c.1196A>C) in the general population?

SEMA4A p.Asp399Ala (c.1196A>C) is very rare (popmax 0.00483%, nfe) (gnomAD).

What do computational predictors say about SEMA4A p.Asp399Ala (c.1196A>C)?

AlphaMissense predicts ambiguous (score 0.4004) — an in-silico prediction, not a clinical call.

SEMA4A p.Asp399Ala

c.1196A>C · rs727504147 · VCV966993

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4004 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00483%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4004	ambiguous
REVEL	0.279	benign-leaning
SaProt	LLR -10.63	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 22 kb · p 0.28 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00483% European (non-Finnish) · 57/1,180,022 alleles

Filtering AF 0.00377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00372% 60/1,614,006 alleles · very rare exomes 56/1,461,870 · genomes 4/152,136 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00483%	20,702
African / African-American	0.00267%	37,454
Remaining individualsnot grpmax-eligible	0.0016%	62,480

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SEMA4A
Protein: p.Asp399Ala
Coding: c.1196A>C
MANE Select: NM_022367
dbSNP: rs727504147
Type: single nucleotide variant
Location: chr1:156172887 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.05
Residue 399: the sema domain

Full SEMA4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SEMA4A p.Asp399Val Uncertain significance ★★ ⚠ same residue
SEMA4A p.Asp399His Uncertain significance ★ same residue
SEMA4A c.*208A>G Uncertain significance ★★ same type
SEMA4A p.Ala114Thr Uncertain significance ★★ ⚠ same type
SEMA4A p.Ala181Thr Uncertain significance ★★ ⚠ same type
SEMA4A p.Ala337Val Uncertain significance ★★ same type
SEMA4A p.Ala446Val Uncertain significance ★★ ⚠ same type
SEMA4A p.Ala509Gly Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/sema4a-p-asp399ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown